Role of the xenobiotic receptor in inflammatory bowel disease

Razvan Arsenescu, Violeta Arsenescu, Jian Zhong, Munira Nasser, Razvan Melinte, R. W.Cameron Dingle, Hollie Swanson, Willem J. De Villiers

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Background: Gene-environment interplay modulates inflammatory bowel diseases (IBD). Dioxin-like compounds can activate the aryl hydrocarbon receptor (AhR) and alter macrophage function as well as T-cell polarization. We hypothesized that attenuation of the AhR signaling pathway will ameliorate colitis in a murine model of IBD. Methods: Dextran sulfate sodium (DSS) colitis was induced in C57BL/6 AhR null mice (AhR-/-), heterozygous mice (AhR-/+), and their wildtype (WT) littermates. Clinical and morphopathological parameters were used to compare the groups. Patients: AhR pathway activation was analyzed in biopsy specimens from 25 IBD patients and 15 healthy controls. Results: AhR-/- mice died before the end of the treatment. However, AhR-/+ mice exhibited decreased disease activity compared to WT mice. The AhR-/+ mice expressed less proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) (6.1- versus 15.7-fold increase) and IL17 (23.7- versus 67.9-fold increase) and increased antiinflammatory IL-10 (2.3-fold increase) compared with the AhR+/+ mice in the colon. Colonic macrophage infiltration was attenuated in the AhR-/+ group. AhR and its downstream targets were significantly upregulated in IBD patients versus control (CYP1A1 -19.9, and IL8- 10-fold increase). Conclusions: Attenuation of the AhR receptor expression resulted in a protective effect during DSS-induced colitis, while the absence of AhR exacerbated the disease. Abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation. Modulation of AhR signaling pathway via the diet, cessation of smoking, or administration of AhR antagonists could be viable strategies for the treatment of IBD. (Inflamm Bowel Dis 2010;)

Original languageEnglish
Pages (from-to)1149-1162
Number of pages14
JournalInflammatory Bowel Diseases
Volume17
Issue number5
DOIs
StatePublished - May 2011

Keywords

  • ER stress
  • Th1
  • Th17
  • Th2
  • adiponectin
  • angiotensin
  • aryl hydrocarbon receptor
  • inflammatory bowel diseases

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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